Is DDHD2 p.Pro18Ala (c.52C>G) pathogenic?

DDHD2 p.Pro18Ala (c.52C>G) is classified Uncertain significance in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-12). AlphaMissense: likely benign (0.0585); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DDHD2 p.Pro18Ala (c.52C>G)?

DDHD2 p.Pro18Ala (c.52C>G) is associated with Inborn genetic diseases (ClinVar).

How common is DDHD2 p.Pro18Ala (c.52C>G) in the general population?

DDHD2 p.Pro18Ala (c.52C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about DDHD2 p.Pro18Ala (c.52C>G)?

AlphaMissense predicts likely benign (score 0.0585) — an in-silico prediction, not a clinical call.

DDHD2 p.Pro18Ala

c.52C>G · rs1804416116 · VCV2306847

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0585 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0585	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -6.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	11.72	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 6.84e-05% 1/1,461,878 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DDHD2
Protein: p.Pro18Ala
Coding: c.52C>G
MANE Select: NM_015214
dbSNP: rs1804416116
Type: single nucleotide variant
Location: chr8:38233046 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 18: the 'disordered' region

Full DDHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DDHD2 p.Pro18Leu Uncertain significance ★ ⚠ same residue
PLPP5 p.Leu18Phe Uncertain significance ★ ⚠ same residue
DDHD2 p.Asp660His Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Arg232Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg329Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg494Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg494Trp Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg595Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ddhd2-p-pro18ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown